Pain
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Neurofibromatosis type 1 (NF1) is the most common of a group of rare diseases known by the term, "Neurofibromatosis," affecting 1 in 3000 to 4000 people. NF1 patients present with, among other disease complications, café au lait patches, skin fold freckling, Lisch nodules, orthopedic complications, cutaneous neurofibromas, malignant peripheral nerve sheath tumors, cognitive impairment, and chronic pain. Although NF1 patients inevitably express pain as a debilitating symptom of the disease, not much is known about its manifestation in the NF1 disease, with most current information coming from sporadic case reports. ⋯ As therapy for NF1 pain remains in various clinical and preclinical stages, we present current treatments available for patients and highlight the importance of future therapeutic development. Equally important, NF1 pain is accompanied by psychological complications in comorbidities with sleep, gastrointestinal complications, and overall quality of life, lending to the importance of investigation into this understudied phenomenon of NF1. In this review, we dissect the presence of pain in NF1 in terms of psychological implication, anatomical presence, and discuss mechanisms underlying the onset and potentiation of NF1 pain to evaluate current therapies and propose implications for treatment of this severely understudied, but prevalent symptom of this rare disease.
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Diabetes mellitus (DM) is a major global health concern, affecting more than 9% of the world population. The most common complication of DM is diabetic peripheral neuropathy (DPN), which leads to neuropathic pain in as many as 50% of patients. Despite its prevalence, there is neither good prevention of nor treatments for DPN, representing a major gap in care for the many who are afflicted. ⋯ It then discusses structural changes in Aβ, Aδ, and C fibers throughout the progression of DPN and their respective contributions to painful DPN in both human patients and DM mouse models. Finally, it highlights remaining questions on sensory neuron structure-function relationships in painful DPN and how we may address these in mouse models by using technological advances in cell-specific modulation. Only when these structure-function relationships are understood, can novel targeted therapeutics be developed for DPN.
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Mechanical allodynia is pain caused by normally innocuous mechanical stimuli and is a cardinal and intractable symptom of neuropathic pain. Roles of low-threshold mechanoreceptors (LTMRs), including Aβ fibers, in mechanical allodynia have previously been proposed, but the necessity and sufficiency of LTMRs in allodynia have not been fully determined. Recent technological advances have made it possible to achieve subpopulation-specific ablation, silencing or stimulation, and to dissect and elucidate complex neuronal circuitry. ⋯ Whole-cell recording has revealed that optical Aβ stimulation after nerve injury causes excitation of lamina I dorsal horn neurons, which are normally silent by this stimulation. Moreover, Aβ stimulation after nerve injury results in activation of central amygdaloid neurons and produces aversive behaviors. In summary, these findings indicate that optogenetics is a powerful approach for investigating LTMR-derived pain (resembling mechanical allodynia) with sensory and emotional features after nerve injury and for discovering novel and effective drugs to treat neuropathic pain.
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Small families carrying rare mutations, which I call "pointer-kindreds," can teach us important lessons. Here, I provide some examples from the field of pain.
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Numerous studies have examined how alexithymia (difficulty identifying and describing one's emotions and a preference for externally oriented thinking) relates to chronic pain and associated disability. We conducted a systematic review and meta-analysis to summarize individual studies that either assessed alexithymia in individuals with chronic pain vs controls or related alexithymia to pain intensity, physical interference, depression, and anxiety. We searched MEDLINE, Embase, and PsycINFO from inception through June 2017; 77 studies met the criteria (valid assessment of alexithymia in adults or children with any chronic pain condition) and were included in analyses (n = 8019 individuals with chronic pain). ⋯ Secondary meta-analyses of 14 studies that conducted partial correlations that controlled for negative affect-related measures revealed that alexithymia was no longer significantly related to pain intensity or interference. Meta-analysis findings demonstrated that alexithymia is elevated in individuals with chronic pain and related to greater pain intensity and physical interference, although the latter relationships may be accounted for by negative affect. Critical future work is needed that examines alexithymia assessed using non-self-report measures, develops a person-centered perspective on this construct, and identifies how alexithymia is relevant to the assessment and treatment of individuals with chronic pain.